Recent human trials report that for patients with established atherosclerotic lesions, vitamin E (E) treatment does not reverse this process, thus concluding that E supplementation does not reduce mortality from coronary heart disease (CHD). Yet, much convincing epidemiological and experimental evidence indicates the potential preventive rather than therapeutic effect of E supplementation on reducing the risk of arteriosclerosis and CHD. To date, no controlled studies have been conducted to demonstrate the preventive role of E supplementation started at an early age on arteriosclerosis. We hypothesize that "supplementation with vitamin E from an early age prevents or retards the development of atherosclerosis and the risk of CHD in individuals with either Western dietary habits (high fat/cholesterol) or a reduced intake of fat and cholesterol." Since long-life E supplementation studies on humans is not practical, we propose testing this hypothesis on a LDL-receptor deficient (LDLR-/-) mouse by feeding mice: a) moderate or b) high fat/cholesterol diet from the age of 5 wks and supplementing both groups' diets with E starting from ages 5 weeks, 6 and 12 mo, to the age of 18 mo. The extent of aortic lesions will be examined by en face microscopic examination, immunohistochemistry, and molecular techniques. The presence and extent of oxidized LDL, macrophages, T cells, and smooth muscle cell populations, as well as endothelial cells expression of adhesion molecules, ICAM-1, VCAM-1, and PCAM-1, will be measured by immunohistochemistry, while aortic expression of mRNA for adhesion molecules as well as inflammatory cytokines and chemokines will be measured by using RT-PCR analysis. In addition, gene chip microarray techniques will be used to determine responsive genes to dietary interventions. The study's results will provide valuable information on the potential preventive role of E supplementation started early in life compared to middle and later ages in reducing the risk of atherosclerosis, the leading cause of morbidity and mortality from CHD in the US.